Although it is generally conceived that selenium status in Americans is sufficient, this is an oversimplified view. Supranutritional levels of selenium may or may not offer health benefit and even promote certain diseases, but 10% adult Americans are estimated to be sub-optimal in body selenium status. There is a knowledge gap in understanding how selenium at nutritional levels of intake prevents type-2 diabetes. Continued existence of this gap represents a health problem because increasing lines of evidence suggest that individuals with sub-optimal selenium are prone to certain chronic diseases including type-2 diabetes. Furthermore, evidence suggests linkages of gut microbiota to body selenium status and type-2 diabetes. Our long-term goal is to understand selenium and selenoprotein functions in age-dependent degeneration. The objective of this proposal is to determine 1) the minimally required dietary selenium for prevention of type-2 diabetes and the underlying mechanisms; 2) the role of gut microbiota in the prevention of type- 2 diabetes by selenium at nutritional levels of intake. The central hypothesis is that optimized body selenium status and gut microbiota prevent type-2 diabetes. The hypothesis has been formulated on the basis of published and preliminary data produced in the applicants' and colleagues' laboratories. The rationale for the proposed research is that once roles of selenium and gut microbiota in type-2 diabetes are better understood, new and innovative approaches to prevent diabetes can be proposed. Guided by strong published and preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Understand the linkage between diabetes prevention and optimized body Se status; 2) Determine roles of gut microbiota in the prevention of type-2 diabetes by optimized Se intake. The proposed research is innovative and significant, because it is expected to vertically advance and expand understanding of selenium interactions with gut microbiota for the primed goal of type-2 diabetes prevention. This will open new avenues towards the nutritional control of diabetes by optimal selenium intake and gut microbiota, especially targeting adult Americans with sub-optimal body selenium status. Additional translational potentials include to advise overweight or obese individuals and residents of low-selenium regions of US, New Zealand, part of Europe and Asia.